Ciprofloxacin is not a better choice in the patients with diabetes suffering urinary tract infection
Kader Ugur1, Isa Ahmet Bal2, Ayse Sagmak Tartar3, Nevzat Gozel4, Bedrettin Orhan5, Emir Donder6, Abdullah Mubin Ozercan7
Abstract
Objective: The aim of this study is to determine antibacterial susceptibilities of Gram-negative bacteria isolated from diabetic and non-diabetic patients as infectious agents of community-acquired urinary tract infections (UTI) and to compare their rates of resistance to the antibiotics frequently used in empirical treatment.
Results: In both diabetic and non-diabetic patient groups, most frequently Escherichia coli (88.5% in diabetic and 85.3% in non-diabetic groups) were isolated. In the diabetic group, microorganisms mostly demonstrated the highest rates of resistance against ampicillin, cephalosporins, ciprofloxacin, amoxicillin-clavulanic acid and in the non-diabetic group ampicillin, amoxicillin-clavulanic acid, cefuroxime and trimethoprim-sulfamethoxazole.
Conclusion: Resistance to ciprofloxacin was at a significantly higher rate in the diabetic group. In diabetic patients, it will be more appropriate to give antibiotherapy in urinary system infections based on the antibacterial susceptibility test results.
Keywords: Diabetes mellitus, urinary tract infection, antibiotic susceptibility.
DOI: 10.5798/dicletip.474694
Yazışma Adresi / Correspondence: Kader Uğur, Endocrinology and Metabolic Diseases, School of Medicine, Firat University, Elazig, Turkey e-mail: kaderaksoy06@hotmail.com
Methods: Ninety-six diabetic and sixty-eight non-diabetic (total n=164) patients’ data were evaluated retrospectively who diagnosed as community-acquired urinary system infection and consulted to outpatient clinics of Department of Endocrinology and Infectious Diseases of Firat University School of Medicine between January 1st , 2014 and December 31st, 2014 whose urine cultures demonstrated Gram-negative bacteria were included in the study.
Antibiotic susceptibilities of the isolated bacteria were determined using Vitek 2 automated system and the results were evaluated as sensitive and resistant.
Original Article / Özgün Araştırma
1 Endocrinology and Metabolic Diseases, School of Medicine, Firat University, Elazig, Turkey ORCID: 0000-0003-4038-2041
2 Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Firat University, Elazig, Turkey ORCID: 0000-0002-0893-8218 3 Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Firat University, Elazig, Turkey ORCID: 0000-0002-9052-7986 4 Internal Medicine, School of Medicine, Firat University, Elazig, Turkey ORCID: 0000-0001-7326-6860
5 Public Health Department of Bursa, Bursa, Turkey ORCID: 0000-0003-3970-2344
6 Internal Medicine, School of Medicine, Firat University, Elazig, Turkey ORCID:0000-0003-2537-6023 7 Gastroenterology, School of Medicine, Firat University, Elazig, Turkey ORCID: 0000-0002-6968-7838 Received: 09.09.2018; Revised: 17.10.2018; Accepted: 25.10.2018
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İdrar Yolu Enfeksiyonu Geçiren Diyabetli Hastalarda Siprofloksasin İyi Bir Seçenek Değildir
Öz
Amaç: Bu çalışmanın amacı diyabetik ve diyabeti olmayan bireylerden izole edilen Gram-negatif bakterilerin toplum kaynaklı idrar yolu enfeksiyonlarının enfeksiyöz ajanları olarak antibakteriyel duyarlılıklarını saptamak ve ampirik tedavide sıklıkla kullanılan antibiyotiklere direnç oranlarını karşılaştırmaktır.
Yöntemler: 1 Ocak- 31 Aralık 2014 tarihleri arasında Fırat Üniversitesi Endokrinoloji ve Enfeksiyon Hastalıkları kliniklerine başvuran toplum kaynaklı idrar yolu enfeksiyonu tanısı almış ve idrar kültürlerinde gram negatif bakteri üremesi olan 96 diyabetik ve 68 diyabetik olmayan hastanın dosyaları retrospektif olarak incelendi. İzole edilen bakterilerin antibiyotik duyarlılıkları, Vitek 2 otomatik sistem kullanılarak belirlenmişti ve sonuçlar duyarlı ve dirençli olarak değerlendirildi.
Bulgular: Hem diyabetik hem de diyabetik olmayan hasta gruplarında en sık Escherichia coli (diyabetiklerde %88,5 ve diyabetik olmayan grupta %85,3) izole edildi. Diyabetik grupta mikroorganizmalar, ampisiline, sefalosporinlere, siprofloksasine, amoksisilin-klavulanik aside ve diyabetik olmayan grup ampisilin, amoksisilin-klavulanik asit, sefuroksim ve trimetoprim-sülfametoksazole karşı en yüksek direnç oranlarını göstermiştir.
Sonuç: Diyabetik grupta Siprofloksasin direnci anlamlı olarak daha yüksekti. Üriner sistem enfeksiyonları olan diyabetik hastalarda, antibiyotik verileceği zaman antibakteriyel duyarlılık testi sonuçlarına dayanarak verilmesi daha uygun olacaktır.
Anahtar kelimeler: Diabetes mellitus, idrar yolu enfeksiyonu, antibiyotik duyarlılığı.
INTRODUCTION
Diabetes mellitus is a metabolic disease characterized by insulin deficiency and ineffectiveness or both. Besides diabetes is a chronic disease increasing in frequency with acute and chronic complications, which also causes serious workforce loss, incurs heavy economic burden and increased morbidity and mortality. In the year 2014, 387 million diabetic patients were living in the world and this number is predicted to rise to 593 million in the year 20351.
In diabetic patients, frequently complicated urinary system diseases are detected. In diabetic patients, symptomatic bacteriuria leads a more severe course. Therefore, accurate diagnosis and appropriate treatment are important2. In diabetic patients, the frequency of UTI is higher than that in the general population. UTI develops more frequently in female, rather than male diabetic patients.
Every year, an average of 8.2% diabetic patients receive the diagnosis of UTI (in women, 12.9% and men, 3.9%)3.
Increased prevalence of bacteriuria and symptomatic UTI in diabetic patients can stem from the difference between diabetic and non- diabetic patients regarding host response and infective characteristics of the bacteria2. Higher glucose concentration in urine may contribute to the development of pathogenic bacteria4. In urinary infections seen in diabetic patients the pathogenic agents are mostly Escherichia coli and other members of the Enterobacteriaceae species5.
In the whole world, in line with the increase in the incidence of type 2 diabetes mellitus, the number of diagnosis of UTI made in these patients also increased which caused a significant increase in health care expenses3. Besides in these patients prescription of broad spectrum antibiotics can trigger the development of antibiotic resistant pathogens6. In urinary system infections as empirical treatment quinolone group of antibiotics are used7. Recently, in our patients whom we followed up in our clinic UTIs caused by resistant pathogens are seen.
The purpose of this study is to determine antibacterial susceptibilities of Gram-negative bacteria isolated from urine cultures of diabetic and non-diabetic patients, which are pathogens of community-acquired urinary system infections, and to compare especially bacterial resistances to antibiotics frequently used in empirical treatment.
Ninety-six diabetic and sixty-eight non-diabetic (total n=164) patients’ data were assessed retrospectively who diagnosed as community- acquired urinary system infection and consulted to outpatient clinics of Department of Endocrinology and Infectious Diseases of Firat University School of Medicine between January 1st , 2014 and December 31st, 2014 whose urine cultures demonstrated Gram-negative bacteria were included in the study. Patients who met 2015 diagnostic criteria8 for diabetes mellitus (DM) set by American Association of Diabetes which are used in routine practice for diagnosis and classification of DM, were enrolled in the study. Result of one urine culture of each patient was evaluated. Patients with nosocomial infections, indwelling urinary catheters and those aged less than 18 years were not included in the study. The protocol of this study was approved by the Ethics Committee of Firat University (meeting 14, issue, 3, dated 06.09.2018). Antibiotic susceptibilities of the isolated bacteria were again determined using Vitek 2 automated system and the results were evaluated as sensitive and resistant.
For the statistical analysis of data SPSS 21.0 package program was used. Parametric data were expressed as means ± standard deviation and categorical data as percentages. For intergroup comparisons categorical data were analyzed using chi-square test and Fisher’s exact chi-square test, while for parametric data Student’s T test was used. For all statistical evaluations p< 0.05 was accepted as the level of significance.
RESULTS
96 diabetic and 68 non-diabetic patients (total n=164) were included in the study.
Demographic data of the patients are presented in Table 1. In both diabetic and non-diabetic patient groups, most frequently Escherichia coli (88.5% in diabetic and 85.3% in non-diabetic groups) and Klebsiella pneumoniae (9.4% and 11.8%, respectively) were isolated. Extended spectrum beta-lactamase (ESBL) produced by pathogenic microorganisms were observed in 20.8% and 13.2% of the patients in the diabetic and non-diabetic groups, respectively.
Distribution of the isolated gram-negative bacteria is given in Table 2.
Table 1: Demographic characteristics of diabetic and non-diabetic patients
Gender Diabetic n (%) Non-diabetic n (%)
Female 90 (93.7) 63 (92.6)
Male 6 (6.3) 5 (7.4)
Total 96 (100) 68 (100)
Average age 61.6±12.6 42.5±15.1
Age Range 29-87 19-75
Table 2: Distribution of isolated Gram-negative bacteria Microorganisms Diabetic group
n (%)
Non- diabetic group n (%)
E. coli 85 (88.5) 58 (85.3)
K. pneumoniae 9 (9.4) 8 (11.8)
Other 2* (2.1) 2** (2.9)
Total 96 (100) 68 (100)
*Pseudomonas aeruginosa and Enterobacter aerogenes
**P. aeruginosa and Proteus mirabilis
According to antibacterial susceptibilities of isolated microorganisms, the most effective antibiotics in both groups were carbapenems, nitrofurantoin, amikacin and piperacillin- tazobactam. In the diabetic group, microorganisms mostly demonstrated the highest rates of resistance against ampicillin, cephalosporins, ciprofloxacin, and amoxicillin- clavulanic acid and in the non-diabetic group ampicillin, amoxicillin-clavulanic acid,
68
cefuroxime and trimethoprim-
sulfamethoxazole in the decreasing order of frequency. Antibacterial susceptibilities of Gram-negative bacteria are shown in Table 3.
Accordingly, in the diabetic group bacterial resistance against ciprofloxacin was greater in the diabetic group (p<0.01). In the diabetic group χ2 value for ciprofloxacin was 9.88. For other antibiotics significant intergroup difference was not detected (for each antibiotic p>0.05).
DISCUSSION
Community-acquired UTI is the most prevalent bacterial infection in the world9. For the treatment of these infections, usually empirical treatment is applied which contributes to the development of resistance. Increase in the resistance against antibiotics frequently used in urinary system infections complicates therapeutic procedures and new treatment alternatives are brought into agenda10. As is already known, immune system of diabetic patients is compromised and their risks of contracting various infections are also enhanced11. When compared with non- diabetics, incidence of symptomatic UTI is higher and more frequently results in complications in diabetics. These infections are generally regarded as complicated infections.
Glycemic regulation, pregnancy, urinary system anomalies, life style factors as sexual activity and other comorbidities potentially effects development of UTIs 2. Diabetic patients carry a higher risk of contracting infections and especially urinary system infections12. Higher incidence of UTIs in diabetics can be explained by decrease in neutrophil response, lower levels of urinary cytokines and leukocyte concentrations which facilitate adhesion of microorganisms to uroepithelial cells13.
Table 3: Antibacterial susceptibilities of Gram-negative bacteria isolated from the urine cultures of diabetic and non-diabetic patients
Antibiotics Diabetic (n=96) n (%)
Non-diabetic (n=68) n (%)
Ampicillin 26 (27.1) 35 (51.4)
Ampicillin-sulbactam 63 (65.6) 52 (76.4) Amoxicillin-clavulanic acid 54 (56.2) 40 (58.8)
Cefuroxime 38 (39.6) 42 (61.7)
Ceftriaxone 38 (39.6) 45 (66.1)
Ceftazidime 40 (41.6) 46 (67.6)
Cefepime 50 (52.1) 50 (73.5)
Gentamicin 87 (88.8) 61 (89.7)
Amikacin 90 (93.7) 68 (100)
Ciprofloxacin* 53 (55.2) 55 (80.8)
Trimethoprim-
sulfamethoxazole 62 (64.5) 44 (64.7)
Nitrofurantoin 93 (96.8) 68 (100)
Piperacillin-tazobactam 86 (89.5) 64 (94.1)
Ertapenem 96 (100) 68 (100)
Imipenem 96 (100) 68 (100)
Meropenem 96 (100) 68 (100)
In our study, as is the case with other studies we found higher incidence of UTI in women relative to men. Treatment of urinary system infection changes dependent on the patient’s age, gender, underlying disease, infectious agent and upper or lower urinary tract involvement. Female gender has been considered to be an independent risk factor for the development of urinary system infection in a diabetic individual14,15. In previous studies advanced age, duration of diabetes and control level of the disease has been described as risk factors. Similarly, body mass index, history of UTI and sexual intercourse has been defined as independent risk factors among diabetics16. In our study, most frequently E. coli was isolated. This result is in compliance with other studies. Based on literature studies in 90% of urinary system infections in diabetic patients pathogenic agent is E. coli17. Antibiotic resistance of uropathogens involving in community-acquired and nosocomial urinary
system infections is gradually increasing18,19. The increase in bacterial resistance rates may be due to the empirically medical prescription, individual self-medication or a low adherence to treatment, inefficient hospital infection control services and poor hygiene. In studies performed, among antibiotics increasing resistance against fluoroquinolones has become evident20. In urinary system infections, broad-spectrum fluoroquinolones are frequently used. Very frequent and unnecessary usages facilitate development of resistance21. In a study performed, E. coli was susceptible to ciprofloxacin and ceftriaxone in 81.8% and 90.9% of the cases, respectively. All of these cases were found to be susceptible to imipenem and in 70% of the cases to trimethoprim-sulfamethoxazole. Clinical features of urinary system infections are similar in diabetic and non-diabetic patients2,22. In diabetic patients, antibiotic resistance against ciprofloxacin used in the treatment of urinary system infections is gradually increasing. Ciprofloxacin resistant E. coli strains responsible for community-acquired and nosocomial urinary infections were compared in the whole world and higher rates of resistance was detected for E. coli strains isolated in nosocomial infections10.
Quinolones belong to an important group of antibiotics used in the empirical treatment of UTIs in adults. Widespread and erroneous use of this group of antibiotics facilitates development of resistance against quinolones in E.coli strains and other microorganisms23. In Turkey, in patients with UTIs who convey risk factors for the development of antibiotic resistance, including especially ciprofloxacin use, necessity of performing urine cultures and antibiotic susceptibility tests have been indicated20. In studies performed in our country, susceptibility rates for ciprofloxacin have been reported to range between 41.1 and 94.2 percent24. In our study, susceptibility rates for ciprofloxacin were found to be 55.2 and
80.8%, in diabetics and non-diabetics, respectively. Ciprofloxacin-resistant bacterial infections have mainly associated with chromosomal mutations that alter DNA gyrase and topoisomerase IV, upregulation of the expression of native efflux pumps, alteration of the amount or porins types and transference of resistance genes by25,26. In our study, we were not able to detect the specific resistance mechanisms.
In various studies performed in our country ampicillin-susceptibility rates of E. coli isolates were found to range between 11.9 and 51 percent27. Higher resistance rates against ampicillin have significantly restricted its use in UTIs. The lowest susceptibility rates in our study were found for ampicillin both in diabetics and non-diabetics (27.1 and 51.4%, respectively). Antibiotic-susceptibility rates for ampicillin-sulbactam and amoxicillin-clavulanic acid were 65.6 and 56.2% in diabetics and 46.4 and 58.8% in non-diabetics, respectively. Since many alternatives exist for the empirical treatment of UTIs, use of these antimicrobials in UTI is contraindicated24.
For a long time, trimethoprim- sulfamethoxazole (SXT) has been used in the treatment of community-acquired UTIs.
However, with increasing rates of antibiotic- resistance among E. coli strains have restricted its use. In studies performed with E. coli strains causing UTIs, susceptibility rates for SXT has been reported to range between 32.5 and 62.5%27. If rates of antibiotic-resistance against SXT among uropathogens exceed 19-20%, then use of trimethoprim-sulfamethoxazole in the empirical treatment of UTIs is not recommended28. In our study, susceptibility rates of SXT were 64.5 and 64.7% in diabetics and non-diabetics, respectively.
One of the frequently used antimicrobials in the treatment of urinary system infections is second- and third-generation oral cephalosporins. In patients complaining of
70 fever and vomiting frequently intramuscular form of ceftriaxone has been preferred. Studies performed in our country, susceptibility rates for ceftriaxone have been reported to vary between 57.1 and 93 percent24. However in our study susceptibility rates for ceftriaxone were found to be 39.6 and 66.1% in diabetics and non-diabetics, respectively. In recent years, increase in the antibiotic-resistance rates may be related to ESBL production in Gram-negative rods especially and predominantly in E. coli and Klebsiella spp. Since limited the number of reports on the use of cephalosporins in Enterobacteriaceae infections are available, before their use in the treatment of UTIs, should be definitely evaluated based on bacterial identification and antibiotic susceptibility test results24.
Antibiotic resistance rates of Escherichia coli against aminoglycosides are relatively lower.
Since they can be administered only through parenteral route and because of their serious side effects, they are employed in limited number of indications23. In our study, susceptibility rates for gentamycin were 88.8%
and 89.7% in diabetics and non-diabetics, respectively.
Nitrofurantoin is an antibacterial agent specific to urinary tract infections. It is a cheap medication in Turkey. A clinically significant resistance against nitrofurantoin has not been observed. As a justification of this lack of clinically significant resistance, its effect on various regions of bacteria has been indicated.
It is effective on many strains of Escherichia coli and enterococci24. In studies performed in our country susceptibility rates for nitrofurantoin were found to range between 64.7 and 97.1%
among E. coli isolates19,24. In our study, antibiotic susceptibility rates for nitrofurantoin were detected as 96.8 and 100% in diabetics and non-diabetics, respectively. Since in many studies performed recently higher antibiotic susceptibility rates for nitrofurantoin have been reported, this drug can be preferred as a
first-line alternative in the treatment of simple cystitis especially on an outpatient basis.
In a study by Vinken et al., the authors detected similar rates of resistance of E. coli isolates in blood and urine cultures of diabetic and non- diabetic patients against ampicillin, trimethoprim-sulfamethoxazole, ciprofloxacin and nitrofurantoin29. Accordingly, we concluded that diabetes per se does not affect sensitivity of antibiotics against uropathogens.
However, the previous study30 in Gondar reported a significant correlation between hyperglycemia, and UTI. This indicates instantaneous determination of fasting blood glucose level may not be associated with bacteriuria. In a study performed by Wang et al.
excepting increased antibiotic resistance against second- and third-generation cephalosporins, the authors observed similar antibiotic resistance profiles in diabetic and non-diabetic patients4. In our study, in the diabetic group microorganisms mostly demonstrated the highest rates of resistance against ampicillin, cephalosporins, ciprofloxacin, and amoxicillin-clavulanic acid and in the non-diabetic group against ampicillin, amoxicillin-clavulanic acid,
cefuroxime, and trimethoprim-
sulfamethoxazole. We detected similar antibiotic resistance profiles in both groups, while in the diabetic group significantly higher antibiotic resistance was noted against ciprofloxacin in the diabetic group (p< 0.01).
Further large scale and glucose level follow-up studies are needed to conclude whether fasting blood glucose level is associated with significant bacteriuria or not.
This study has some limitations which have to be pointed out. The small patient population and the retrospective nature of the study do not allow us to well interpret regarding on clinical complaints, gender, comorbid conditions and asymptomatic bacteriuria treatment options.
However, this present work will be the subject of ongoing studies. In the future, we therefore
think that such studies would be more appropriate in clinically well-defined prospective patient groups by using diagnostic accuracy using laboratory and clinical algorithms. Even with the above-mentioned limitations, this study showed that there was a clear relationship between urinary tract infections and Cipro resistance.
In conclusion, E. coli is the most frequent cause of community-acquired infections. We detected significantly higher antibiotic resistance in the diabetic group against ciprofloxacin which is frequently used in our country in the empirical treatment of urinary system infections.
Awareness is needed of both the population and health professionals about the importance for the correct use of antibiotics, and it is very important to take into account the result of antibiotics susceptibility tests. As a more correct approach, in the empirical treatment of urinary system infections in diabetic patients, quinolones should not be preferred and treatment planning should be made based on the results of the antibiotic susceptibility test results.
Conflict of interest
There is no conflict of interest.
Ethical standard Approval was obtained from the Ethics Committee of Firat University (meeting 14, issue, 3, dated 06.09.2018)
Declaration of Conflicting Interests: The authors declare that they have no conflict ofinterest.
Financial Disclosure: No financial support was received.
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